Physiology of the Prolactin Releasing Peptides

描述(由申请人提供)：这是一个重新修订的，竞争性更新申请(HL66023)，继续我们对最近描述的神经肽的生理相关性的检查，我们已经证明这些神经肽至少在药理上通过大脑作用部位刺激应激激素分泌(催乳素、催乳素和促肾上腺皮质激素)。此外，这些多肽刺激与压力相关的行为反应(活动)，至少有一个在大脑中起作用，刺激交感神经活动，导致血压升高。这些肽(催乳素释放肽，PrRP；神经肽W，NPW；神经肽B，NPB)由大脑中不同的神经元群产生，其中许多支配下丘脑室旁核(PVN)、弓状核(ARC)以及下丘脑腹内侧核和背内侧核(VMH/DMH)。所有这三种多肽都存在于支配下丘脑和脑干自主神经中心的神经元中。我们的目标是了解这些多肽在下丘脑和下丘脑外对应激反应中所起的作用。我们解决了多个特定的目标，所有这些都与创始假设有关，即在某些应激模式下，这些多肽中的一个或多个对于内分泌和/或心血管反应是必不可少的。我们的方法是用电生理学、药理学和单细胞RT-PCR方法证明这些肽对已识别的前脑和后脑神经元[如PVN、ARC、VMH/DMH、孤束核(NTS)、延髓吻侧(RVLM)和迷走神经背侧运动核]的直接影响。然后，我们将尝试折衷多肽产生，并检查对身体应激的激素分泌以及对高血压和低血压挑战的心血管反应(即压力感受性反射敏感性)。了解控制压力反应的正常机制将揭示在人类群体中管理压力的潜在策略，以及这种压力对心血管和代谢的影响。这些研究还可能提供对代谢综合征(X综合征)发展的核心机制的洞察，该综合征的特征是肥胖、血糖控制不良、代谢和自主神经功能改变以及有不良心血管后果的倾向。此外，这些研究将进一步深入了解荷尔蒙和自主神经对压力的协调反应。

DESCRIPTION (provided by applicant): This is a rerevised, competitive renewal application (HL66023) that continues our examination of the physiologic relevance of recently described neuropeptides which we have demonstrated to act at least pharmacologically to stimulate stress hormone secretion (prolactin, PRL, and adrenocorticotropin, ACTH) by a brain site of action. Additionally, these peptides stimulate stress-related behavioral responses (activity) and at least one acts in brain to stimulate sympathetic activity resulting in increased blood pressure. These peptides (prolactin releasing peptide, PrRP; neuropeptide W, NPW; and neuropeptide B, NPB) are produced in separate populations of neurons in brain, many of which innervate the hypothalamic paraventricular nucleus (PVN), arcuate nucleus (ARC) and ventromedial and dorsomedial hypothalamic nuclei (VMH/DMH). All three peptides are contained in neurons that innervate autonomic centers in hypothalamus and brain stem. It is our goal to understand the roles these peptides play in the hypothalamic and extrahypothalamic responses to stress. We address multiple specific aims all related to the founding hypothesis that one or more of these peptides is essential for the endocrine and/or cardiovascular response to stress, under certain paradigms of stress. Our approach will be to demonstrate direct effects of these peptides on identified fore- and hindbrain neurons [e.g. in PVN, ARC, VMH/DMH, nucleus tractus solitarius (NTS), rostral lateral medulla (RVLM), and dorsal motor nucleus of the Vagus] using electrophysiologic, pharmacologic and single cell RT- PCR approaches. We will then attempt compromise of peptide production and examine hormone secretion in response to physical stress and the cardiovascular response to hypertensive and hypotensive challenge (i.e. baroreflex sensitivity). Understanding the normal mechanisms controlling the response to stress will reveal potential strategies for the management of stress in the human population and the cardiovascular and metabolic consequences of that stress. These studies may also provide insight into the central mechanisms contributing to development of the metabolic syndrome (Syndrome X), which is characterized by obesity, poor glycemic control, altered metabolic and autonomic function and a propensity for adverse cardiovascular outcomes. Additionally, these studies will provide further insight into the coordinated hormonal and autonomic responses to stress.